Hepatitis B Virus (HBV) and Hepatitis C Virus (HCV) are major public health problems, causing more than an estimated 500 million chronic infections worldwide. Both viruses are a source of progressive liver disease, and are the major risk factors for nearly all cases of primary hepatocellular carcinoma [Chen, S. L., Morgan, T. R., Int. J. Med. Sci. 3, 47-52 (2006); Lavanchy, D., J. Viral. Hepat. 11, 97-107 (2004); Wong, S. N., Lok, A. S., Curr. Opin. Gastroenterol. 22, 241-247 (2006)]. Licensed standards of care for both viral infections, while effective in many cases, are sub-optimal and do not result in virologic or clinical ‘cures’ in most individuals [Wong and Lok (2006)]. The development of drug-resistance in HBV, including strains carrying resistance to multiple licensed agents is an emerging clinical problem, and drug-resistance for future HCV therapies is predicted to be a significant clinical issue [Tomei, L. et al., Antivir. Chem. Chemother. 16, 225-245 (2005); Tong et al., Antivir. Res. 70, 28-38 (2006); Yim et al., Hepatology 44, 703-712 (2006)]. Thiazolide compounds such as nitazoxanide (NTZ) are anti-infective and possess activity against anaerobic bacteria, protozoa and viruses [Rossignol, J. F. Santoro, M. G. et al., J. Biol. Chem., 284, 29798-29808 (2009); Korba, B. E. et al. Antiviral Res. 77, 56-63 (2008); Fox, L. M., Saravolatz, L. D., Clin. Infect. Dis. 40, 1173-1180 (2005); Pankuch, G. A., Appelbaum, P. C., Antimicrob. Agents Chemother. 50, 112-117 (2006); Rossignol, J. F. et al., Lancet 368, 124-129 (2006); Rossignol and El-Gohary, Aliment. Pharmacol. Ther. 24, 1423-1430 (2006)]. Originally developed as a treatment of intestinal protozoan infections, the antiviral properties of NTZ were discovered during the course of its development for treating cryptosporidiosis in patients with acquired immune deficiency syndrome (AIDS).
NTZ is marketed in the United States for treating diarrhea and enteritis caused by Cryptosporidium spp or Giardia lamblia in adults and children down to 12 months of age (Alinia®, Romark Laboratories, Tampa, Fla. USA). Clinical trials have demonstrated effectiveness of NTZ in treating diarrhea and enteritis associated with enteric protozoan infections caused by Cryptosporidium spp, G. lamblia, Entamoeba histolytica and Blastocystis hominis [Amadi et al., Lancet 360, 1375-1380. (2002); Oritz et al., Aliment. Pharmacol. Ther. 15, 1409-1415. (2001); Rossignol. J. F. et al., J. Infect. Dis. 184, 381-384 (2001); Clin. Gastroenterol. Hepatol. 3, 987-991. (2005), Clin. Gastroenterol. Hepatol. 4, 320-324. (2006)]. Recent randomized double-blind clinical trials have demonstrated effectiveness of NTZ in treating Clostridium difficile colitis in adults, rotavirus gastroenteritis in young children, and rotavirus and norovirus gastroenteritis in adults [Musher et al., Clin. Infect. Dis. 43, 421-427 (2006); Rossignol et al, Lancet 368, 124-129 (2006); Rossignol and El Gohary, Aliment. Pharmacol. Ther. 24, 1423-1430 (2006)].
The mechanism of action of NTZ against anaerobic organisms is attributed to interference with pyruvate:ferredoxin oxidoreductase (PFOR) enzyme-dependent electron transfer reactions, which are essential for anaerobic energy metabolism [Hoffman et al., Antimicrob. Agents Chemother. 51, 868-876 (2006)]. The mechanism of antiviral activity of NTZ against hepatitis B and C has not been fully elucidated, although recent studies suggest host cell-related protein modulation. In the RNA viruses such as influenza A [Rossignol J. F. and Santoro M. G. (2009)] and HCV [Elazar M., et al. Gastroenterology, 137, 1827-1835 (2009)], NTZ selectively leads to inhibition of viral glycoproteins at the post-translational level, preventing final assembly of the virus before exiting the cell to infect another cell. Also in HCV, NTZ and other thiazolide analogs cause an increase in eIF2α phosphorylation induced by PKR activation, which are key mediators of intracellular host antiviral activity [Elazar M. (2009].
Following oral administration of a 500 mg tablet, NTZ is partially absorbed from the gastrointestinal tract and rapidly hydrolyzed in plasma to form its active circulating metabolite, tizoxanide (TIZ). NTZ is not detected in plasma. Maximum serum concentrations of TIZ, reach approximately 10 μg/mL (37 μM) [Stockis et al., Int. J. Clin. Pharmacol. Ther. 40, 221-227 (2002)] following oral administration of one 500 mg NTZ tablet (Alinia®) with food. TIZ is glucurono-conjugated in the liver and excreted in urine and bile. Approximately two-thirds of an oral dose pass through the intestinal tract and is excreted in feces as TIZ [Broekhuysen, J. et al., Int. J. Clin. Pharmacol. Ther. 38, 387-394 (2000)]. The elimination half-life of TIZ from plasma is approximately 1.5 hours. TIZ does not inhibit cytochrome P450 enzymes, and therefore, no drug-drug interactions are expected [Broekhuysen et al., 2000; Stockis et al. (2002)]. The most commonly reported side-effects in clinical trials include mild abdominal pain, headache, diarrhea and nausea, which occur at rates similar to those reported for patients receiving placebo. While most of the clinical experience with NTZ has involved a 3 to 14 day treatment regimen, continued use of the drug for periods as long as 4 years has been evaluated in patients with AIDS-related cryptosporidiosis without any significant drug-related adverse events [Fox, L. M., Saravolatz, L. D. (2005); Rossignol and El-Gohary (2006)].
The present application relates generally to the field of alkylsulfinyl thiazolide compounds. In particular, the antiviral activity of certain alkylsulfinyl thiazolide compounds is demonstrated against HCV compared to the antiviral activity of structurally related thiazolides Nitazoxanide (NTZ), Tizoxanide (TIZ) respectively.

We disclosed a novel class of alkylsulfonyl-substituted thiazolides, e.g., RM4863, RM5015, their analogs and prodrugs, in US 2009/0036467 A1, which is hereby incorporated by reference in its entirety. The inventive compounds have demonstrated utility against inhibitor of HCV replication in cell culture.

As opposed to the 5-nitrothiazolide series of compounds exemplified by NTZ and TIZ, acetate and related prodrugs of several other thiazolides including the alkylsulfonyl-substituted analogs are essentially inactive in HCV cell culture assays. The simple acetate prodrugs RM4864 and RM5014 are metabolically stable under the cell assay conditions and are not being hydrolyzed by cellular esterases to the parent phenolic drugs RM4863 and RM 5015, respectively in any appreciable amount.